The natural history of Efavirenz Drug Induced liver injury

Background Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor (NNRTI), has been a component of first line antiretroviral treatment in the South African HIV/AIDS programme since 2004. Similarly, it is extensively used in ART programmes in other low and middle incomes countries. The natural history of the previously reported EFV drug induced liver injury (DILI), is unknown. Objectives To establish causality assessment for the drug-induced liver injury and elucidate the natural history of EFV DILI by observing a cohort of patients through documenting all the factors influencing the patterns of clinical and histological injury, the time to clinical and biochemical recovery, the associated mortality rate and to establish if any demographic or clinical factors predict poor outcomes. Methods Patients were prospectively included after establishing causality criteria for EFV DILI. Clinical, demographic and histological features were carefully documented from the time of presentation and through follow up. Prednisone at 0.25-0.5mg/kg was initiated at the discretion of the treating hepatologist. Risk factors for severe injury or death and time to event (full clinical recovery and full biochemical recovery) were analyzed. Results 50 patients were included in the analysis, median age 34 (IQR 29-39) years, men significantly older than women, p=0.014. Most (92%) were female gender, and of black African ethnicity (86%). The median duration on ART at time of presentation was 6.5 months with half of the women initiating ART during pregnancy at a median gestation of 24 weeks (IQR 11 – 36). Median CD4 nadir at ART treatment initiation was 517 cells/mm3, with no significant difference (p=NS) in CD4 nadir in those pregnant or not. Median RUCAM score was 7 and of the 66% of patients who had liver biopsies, 3 histological patterns were identified: submassive necrosis (57,5%), nonspecific hepatitis (36%) and mixed cholestatic hepatitis (6%). Multivariate analysis suggested predictors for the development of submassive necrosis included age >30 years [OR 0.86 (0.15-0.97), p=0.02], pregnancy [OR 6.9 (1.34 – 35.6), p=0.02]; CD4 >350 [OR, 7.1 (1.5-31.9), p=0.02] but not alcohol use [OR 1.17 (0.72-1.18); p=0.07]. For the non-specific hepatitis group, only pregnancy predicted [OR 8.7 (1.3- 58.2), p=0.03]. The mortality rate was 14%, median time from admission to death was 15 days with the median duration to initial hospital discharge 33 (IQR 24 -52) days. Biochemical recovery was prolonged necessitating a follow up period of more than a year at an outpatient specialist clinic. 86% initiated protease inhibitor based ART successfully. Conclusion EFV DILI is a severe injury with significant inpatient mortality and morbidity requiring prolonged hospitalization and outpatient follow up

Count me in: an inclusive approach towards patient recruitment for clinical research studies in the NHS

Background: Participation in clinical research is associated with better patient outcomes and higher staff retention and satisfaction rates. Nevertheless, patient recruitment to mental health studies is challenging due to a reliance on clinician or patient referrals (standard approach). To empower patients and make healthcare research more equitable, we explored a novel researcher-led approach, called ‘Count Me In’ (CMI). Objective: To evaluate a 12-month implementation of CMI in a routine clinical setting. Methods: CMI was launched in August 2021 in a mental health National Health Service (NHS) Trust in England. Patients (aged 18+) learnt about CMI at their initial clinical appointment. Unless they opted out, they became contactable for research (via research informatics searches). Findings: After 12 months, 368 patients opted out and 22 741 became contactable through CMI, including 2716 through the standard approach and 20 025 through electronic searches (637% increase). Of those identified via electronic searches, 738 were contacted about specific studies and 270 consented to participate. Five themes were identified based on patient and staff experiences of CMI: ‘level of awareness and accessibility of CMI’, ‘perceptions of research and perceived engagement with CMI’, ‘inclusive research practice’, ‘engagement and incentives for research participation’, and ‘relationships between clinical and research settings’. Conclusions: CMI (vs standard) led to a larger and diverse patient cohort and was favoured by patients and staff. Yet a shift in the NHS research culture is needed to ensure that this diversity translates to actual research participation. Clinical implications: Through collaboration with other NHS Trusts and services, key funders (National Institute for Health and Care Research) and new national initiatives (Office for Life Sciences Mental Health Mission), CMI has the potential to address recruitment challenges through rapid patient recruitment into time-sensitive country-wide studies

Count me in : an inclusive approach towards patient recruitment for clinical research studies in the NHS

Background. Participation in clinical research is associated with better patient outcomes and higher staff retention and satisfaction rates. Nevertheless, patient recruitment to mental health studies is challenging due to a reliance on clinician or patient referrals (standard approach). To empower patients and make healthcare research more equitable, we explored a novel researcher-led approach, called ‘Count Me In’ (CMI). Objective. To evaluate a 12-month implementation of CMI in a routine clinical setting. Methods. CMI was launched in August 2021 in a mental health National Health Service (NHS) Trust in England. Patients (aged 18+) learnt about CMI at their initial clinical appointment. Unless they opted out, they became contactable for research (via research informatics searches). Findings. After 12 months, 368 patients opted out and 22 741 became contactable through CMI, including 2716 through the standard approach and 20 025 through electronic searches (637% increase). Of those identified via electronic searches, 738 were contacted about specific studies and 270 consented to participate. Five themes were identified based on patient and staff experiences of CMI: ‘level of awareness and accessibility of CMI’, ‘perceptions of research and perceived engagement with CMI’, ‘inclusive research practice’, ‘engagement and incentives for research participation’, and ‘relationships between clinical and research settings’. Conclusions. CMI (vs standard) led to a larger and diverse patient cohort and was favoured by patients and staff. Yet a shift in the NHS research culture is needed to ensure that this diversity translates to actual research participation. Clinical implications. Through collaboration with other NHS Trusts and services, key funders (National Institute for Health and Care Research) and new national initiatives (Office for Life Sciences Mental Health Mission), CMI has the potential to address recruitment challenges through rapid patient recruitment into time-sensitive country-wide studies

Clinical features and outcomes of COVID-19 admissions in a population with a high prevalence of HIV and tuberculosis: a multicentre cohort study

Background There is still a paucity of evidence on the outcomes of coronavirus disease 2019 (COVID-19) among people living with human immunodeficiency virus (PWH) and those co-infected with tuberculosis (TB), particularly in areas where these conditions are common. We describe the clinical features, laboratory findings and outcome of hospitalised PWH and human immunodeficiency virus (HIV)-uninfected COVID-19 patients as well as those co-infected with tuberculosis (TB). Methods We conducted a multicentre cohort study across three hospitals in Cape Town, South Africa. All adults requiring hospitalisation with confirmed COVID-19 pneumonia from March to July 2020 were analysed. Results PWH comprised 270 (19%) of 1434 admissions. There were 47 patients with active tuberculosis (3.3%), of whom 29 (62%) were PWH. Three-hundred and seventy-three patients (26%) died. The mortality in PWH (n = 71, 26%) and HIV-uninfected patients (n = 296, 25%) was comparable. In patients with TB, PWH had a higher mortality than HIV-uninfected patients (n = 11, 38% vs n = 3, 20%; p = 0.001). In multivariable survival analysis a higher risk of death was associated with older age (Adjusted Hazard Ratio (AHR) 1.03 95%CI 1.02–1.03, p < 0.001), male sex (AHR1.38 (95%CI 1.12–1.72, p = 0.003) and being “overweight or obese” (AHR 1.30 95%CI 1.03–1.61 p = 0.024). HIV (AHR 1.28 95%CI 0.95–1.72, p 0.11) and active TB (AHR 1.50 95%CI 0.84–2.67, p = 0.17) were not independently associated with increased risk of COVID-19 death. Risk factors for inpatient mortality in PWH included CD4 cell count < 200 cells/mm3, higher admission oxygen requirements, absolute white cell counts, neutrophil/lymphocyte ratios, C-reactive protein, and creatinine levels. Conclusion In a population with high prevalence of HIV and TB, being overweight/obese was associated with increased risk of mortality in COVID-19 hospital admissions, emphasising the need for public health interventions in this patient population

Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

In the version of this article initially published, the author affiliations incorrectly listed “Candiolo Cancer Institute FPO-IRCCS, Candiolo (TO), Italy” as “Candiolo Cancer Institute, Candiolo, Italy.” The change has been made to the HTML and PDF versions of the article

Risk factors for Coronavirus disease 2019 (Covid-19) death in a population cohort study from the Western Cape province, South Africa

Risk factors for coronavirus disease 2019 (COVID-19) death in sub-Saharan Africa and the effects of human immunodeficiency virus (HIV) and tuberculosis on COVID-19 outcomes are unknown. We conducted a population cohort study using linked data from adults attending public-sector health facilities in the Western Cape, South Africa. We used Cox proportional hazards models, adjusted for age, sex, location, and comorbidities, to examine the associations between HIV, tuberculosis, and COVID-19 death from 1 March to 9 June 2020 among (1) public-sector “active patients” (≥1 visit in the 3 years before March 2020); (2) laboratory-diagnosed COVID-19 cases; and (3) hospitalized COVID-19 cases. We calculated the standardized mortality ratio (SMR) for COVID-19, comparing adults living with and without HIV using modeled population estimates.Among 3 460 932 patients (16% living with HIV), 22 308 were diagnosed with COVID-19, of whom 625 died. COVID19 death was associated with male sex, increasing age, diabetes, hypertension, and chronic kidney disease. HIV was associated with COVID-19 mortality (adjusted hazard ratio [aHR], 2.14; 95% confidence interval [CI], 1.70–2.70), with similar risks across strata of viral loads and immunosuppression. Current and previous diagnoses of tuberculosis were associated with COVID-19 death (aHR, 2.70 [95% CI, 1.81–4.04] and 1.51 [95% CI, 1.18–1.93], respectively). The SMR for COVID-19 death associated with HIV was 2.39 (95% CI, 1.96–2.86); population attributable fraction 8.5% (95% CI, 6.1–11.1)

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

A replicon RNA vaccine can induce durable protective immunity from SARS-CoV-2 in nonhuman primates after neutralizing antibodies have waned.

The global SARS-CoV-2 pandemic prompted rapid development of COVID-19 vaccines. Although several vaccines have received emergency approval through various public health agencies, the SARS-CoV-2 pandemic continues. Emergent variants of concern, waning immunity in the vaccinated, evidence that vaccines may not prevent transmission and inequity in vaccine distribution have driven continued development of vaccines against SARS-CoV-2 to address these public health needs. In this report, we evaluated a novel self-amplifying replicon RNA vaccine against SARS-CoV-2 in a pigtail macaque model of COVID-19 disease. We found that this vaccine elicited strong binding and neutralizing antibody responses against homologous virus. We also observed broad binding antibody against heterologous contemporary and ancestral strains, but neutralizing antibody responses were primarily targeted to the vaccine-homologous strain. While binding antibody responses were sustained, neutralizing antibody waned to undetectable levels in some animals after six months but were rapidly recalled and conferred protection from disease when the animals were challenged 7 months after vaccination as evident by reduced viral replication and pathology in the lower respiratory tract, reduced viral shedding in the nasal cavity and lower concentrations of pro-inflammatory cytokines in the lung. Cumulatively, our data demonstrate in pigtail macaques that a self-amplifying replicon RNA vaccine can elicit durable and protective immunity to SARS-CoV-2 infection. Furthermore, these data provide evidence that this vaccine can provide durable protective efficacy and reduce viral shedding even after neutralizing antibody responses have waned to undetectable levels